Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklion, Greece.
Laboratory of Gastroenterology, School of Medicine, University of Crete, Heraklion, Greece.
Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):891-899. doi: 10.1016/j.bbadis.2017.12.031. Epub 2017 Dec 26.
BACKGROUND & AIMS: TGFβ superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells, where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased.
We studied the effect of activin-A on mouse primary Kupffer cells (KCs) and Hepatic Stellate cells (HSCs) and the levels of activin-A and its inhibitor follistatin in the serum of patients from a large panel of liver diseases.
Activin-A is expressed by mouse hepatocytes, HSCs and Liver Sinusoid Endothelial cells but not KCs. Each cell type expresses different activin receptor combinations. HSCs are unresponsive to activin-A due to downregulation/desensitization of type-II activin receptors, while KCs respond by increasing the expression/production of TNFα και TGFβ1. In the presence of KCs or conditioned medium from activin-A treated KCs, HSCs switch to a profibrogenic phenotype, including increased collagen and αSMA expression and migratory capacity. Incubation of activin-A treated KC conditioned medium with antibodies against TNFα and TGFβ1 partially blocks its capacity to activate HSCs. Only patients with alcoholic liver diseases and NASH cirrhosis have significantly higher activin-A levels and activin-A/follistatin ratio.
Activin-A may induce fibrosis in NASH and alcoholic cirrhosis via activation of KCs to express pro-inflammatory molecules that promote HSC-dependent fibrogenesis and could be a target for future anti-fibrotic therapies.
TGFβ 超家族成员激活素-A 是一种多功能激素/细胞因子，在多种组织和细胞中表达，调节细胞分化、增殖、炎症和组织结构。在酒精性肝硬化和非酒精性脂肪性肝炎（NASH）中报道了高激活素-A 水平。我们的目的是鉴定激活素-A 在肝脏纤维化过程中涉及的细胞类型，并验证该分子可在增加的肝脏疾病中发现。
我们研究了激活素-A 对小鼠原代枯否细胞（KCs）和肝星状细胞（HSCs）的影响，以及在来自大量肝脏疾病患者的血清中激活素-A 及其抑制剂卵泡抑素的水平。
激活素-A 由小鼠肝细胞、HSCs 和肝窦内皮细胞表达，但不表达于 KCs。每种细胞类型表达不同的激活素受体组合。由于 II 型激活素受体的下调/脱敏，HSCs 对激活素-A 无反应，而 KCs 通过增加 TNFα 和 TGFβ1 的表达/产生来反应。在 KCs 或激活素-A 处理的 KCs 条件培养基存在下，HSCs 转变为促纤维化表型，包括胶原和αSMA 表达和迁移能力增加。用抗 TNFα 和 TGFβ1 抗体孵育激活素-A 处理的 KC 条件培养基可部分阻断其激活 HSCs 的能力。只有患有酒精性肝病和 NASH 肝硬化的患者才有明显更高的激活素-A 水平和激活素-A/卵泡抑素比值。
激活素-A 可能通过激活 KCs 表达促炎分子来诱导 NASH 和酒精性肝硬化的纤维化，促进 HSC 依赖性纤维化，并可能成为未来抗纤维化治疗的靶点。
